Preventive or therapeutic drugs for fibrosis containing chymase inhibitors as the active ingredient

ABSTRACT

A medicament for the prevention or treatment containing a chymase inhibitor, as an effective component, which is a side effect-free, safe medicament for prevention or treatment of fibrosis of the skin or various viscera which suppresses the progression of the condition, prevents the progression of complications, and improves the quality of life of the patient, wherein a quinazoline derivative having the formula (I):  
                 
 
     or a pharmaceutically acceptable salt thereof is included therein.

TECHNICAL FIELD

[0001] The present invention relates to a medicament for the preventionor treatment of fibrosis involving extracellular matrix dysbolism, apharmaceutical composition for the prevention or treatment of fibrosisinvolving extracellular matrix dysbolism, and a medicament foralleviation of extracellular matrix dysbolism.

BACKGROUND ART

[0002] Fibrosis is a disease characterized by excessive deposition ofconnective tissue protein involving extracellular matrix dysbolism inthe skin and other organs such as the lungs, heart, liver, and kidneys.For example, hepatic fibrosis is a disease characterized by theexcessive deposition of collagen and other connective tissue proteins inthe liver. Diseases leading to hepatic fibrosis include vairalhepatitis, alcoholic liver disease, schistosomiasis etc. In thesediseases, the connective tissue protein gradually accumulates in thehepatic tissue. As a result, disorders in the hepatic functions occurand finally lead to cirrhosis (J. Hepatol. 8, 115, 1989). On the otherhand, scleroderma and other skin fibrosis are conditions characterizedby the excessive deposition of collagen and other connective tissueprotein in the epidermis of the skin. The cause of skin fibrosisincludes various skin diseases such as chronic inflammation and chronicautoimmune reactions, and various skin injury such as mechanical woundsand burns (J. Rheumatol. 15, 202, 1988). Further, pulmonary fibrosis isa condition characterized by the excessive deposition of collagen orother connective tissue proteins in the lungs and is induced bypneumonia medicamentosa caused by chemotherapeutic agents such asanti-tumor drugs and antibiotics (Am. J. Pathol. 259, L159, 1990).

[0003] The mechanism of pathogenesis of fibrosis have not yet beensufficiently elucidated at the present. In general, the proliferationand function of fibroblasts are closely controlled in normal conditions.However, in pathological state in which inflammation or tissue injury isserious or sustained, the tissue repair mechanism goes into overdriveand the control mechanism is abrogated (Int. J. Biochem. Cell Biol. 29,79, 1997). Excessive tissue repair is caused by over-production ofconnective tissue protein probably due to abnormal proliferation offibroblasts and extracellular matrix dysbolism. The cytokines causingsuch a phenomenon include, fibroblast growth factor (FGF family),transforming growth factor (TGF-β), platelet derived growth factor(PDGF), etc. (FASEB J. 8, 854, 1994). In recent years, numerous studieshave been performed to obtain the substances inhibiting the productionor the activity of such cytokines, but no inhibitors have yet beenapplied to human. Further, anti-inflammatory agents such as steroid havebeen used to treat fibrosis with the aim of suppressing chronicinflammation, but they cannot be said to be sufficiently satisfactory interms of efficacy and side effects. A superior medicament for thetreatment of fibrogenesis is therefore needed.

[0004] On the other hand, chymase is a serine protease stored in mastcell granules, and widely present in tissue such as the skin, heart,vascular walls, intestines, etc. (Mast Cell Proteases in Immunology andBiology; Caughey, G. H., Ed; Marcel Dekker, Inc.; New York, 1995).Numerous findings that suggest chymase is involved in various types offibrosis have already been reported. For example, it has been reportedthat administration of cromoglycate, an inhibitor for mast celldegranulation, suppresses skin fibrosis in Tsk (tight skin) mice, ananimal model for scleroderma (Am. J. Pathol. 82, 493, 1976) (J.Rheumatol. 14, 299, 1987). Furthermore, it has been reported thatchymase activity is increased in Tsk mice (Jp. J. Pharmacol. 97 (sup. I)60P, 1998), and that there is a correlation between the severity of theskin fibrosis and the number of skin mast cells in a bleomycin-inducedscleroderma model in mice (Clin. Immunol. 92, 6, 1999). Regardingpulmonary fibrosis, in addition, it is known that pulmonary fibrosis isnot induced by administration of bleomycin in mast cell deficient mice,suggesting involvement of mast cells that produce chymase (AgentsActions 39, 20, 1993). Further, regarding hepatic fibrosis, the numberof mast cells in human livers increases along with the fibrogenesis oflivers (J. Hepatol. 26, 1042, 1997). A similar increase of mast cells isobserved even in various hepatic fibrosis models (Hepatology 23, 888,1996, J. Hepatol. 29, 112, 1998). In biliary cirrhosis model in rat,mast cell degranulation are observed in the liver, showing theinvolvement of mast cell granular components such as chymase inpathogenesis of fibrosis (Hepatology 23, 888, 1996). Regarding theinvolvement of chymase in fibrogenesis of the heart, on the other hand,it has been reported that chymase activity is 5-fold in thepressure-overloaded hamster heart in which fibrosis and apoptosis areobserved (FEBS lett. 406, 301, 1997). Recently, it has been shown thatrat mast cell chymase (RMCP-1) causes apoptosis of cardiomyocytesderived from neonatal rats, suggesting that chymase may play a role incell death of cardiomyocytes and fibrogenesis during progression ofheart failure (Circulation 100, 1443, 1999). Further, it has also beenreported that the expression of mRNA of chymase is augmented in the endstage where fibrogenesis becomes prominent in a canine with heartfailure induced by rapid right ventricular pacing (Matsumoto et al.,73rd Scientific Sessions of American Heart Association, November 2000,New Orleans, Abs. 2191). Restenosis following PTCA is a vascular diseaseassociated with fibrosis. It has been reported that an increase in mastcells augmentation of expression of chymase is observed inballoon-injured artery in dog, and that tranilast that inhibits mastcell degranulation suppresses neointima formation in this model(Circulation 99, 1084, 1999). However, there is also a report thatbleomycin induced pulmonary fibrosis is induced even in mastcell-deficient mice in the same way as normal mice (Lab. Invest. 78,1431, 1998). There are still many unclear points in the role of mastcells or chymase in various types of fibrosis.

[0005] There are findings suggesting the mechanism of action of chymasein fibrosis. For example, it has been reported that chymase promotes inculture the production of TGF-β, the major cytokine for fibrogenesis (J.Biol. Chem. 270, 4689, 1995). Further, there is a report that chymaseacts in vitro on procollagen, a precursor of collagen, to promotecollagen fibril formation (J. Biol. Chem. 272, 7127, 1997) and a reportthat chymase activates procollagenase (Biochem. J. 305, 301, 1995).

[0006] At the present time, a broad search is under way for substanceswhich can inhibit chymase activity in animal models with the aim ofelucidating the role of chymase in the body.

[0007] There are chymase inhibitors such as low molecular weight chymaseinhibitors such as shown in print (Protease Inhibitors; Barrett et al.,Eds; Elssevier Science B. V.; Amsterdam, 1996), a-keto acid derivativesreported as peptide type inhibitors (WO93-25574, Proc. Natl. Acad. Sci.USA, 1995, 92, 6738), α,α-difluoro-β-keto acid derivatives (JapaneseUnexamined Patent Publication (Kokai) No. 9-124691), tripeptideinhibitors (WO93-03625), phosphoric acid derivatives (Oleksyszyn et al.,Biochemistry 30, 485, 1991), peptide like inhibitors such astrifluoromethylketone derivatives (WO96-33974, Japanese unexaminedPatent Publication (Kokai) No. 10-53579) and acetoamide derivatives(Japanese Unexamined Patent Publication (Kokai) No. 10-7661, JapaneseUnexamined Patent Publication (Kokai) No. 10-53579, Japanese UnexaminedPatent Publication (Kokai) No. 11-246437, WO99-41277, WO98-18794,WO96-39373), non-peptide type inhibitors such as triazine derivatives(Japanese Unexamined Patent Publication (Kokai) No. 8-208654 andJapanese Unexamined Patent Publication (Kokai) No. 10-245384), phenolester derivatives (Japanese Unexamined Patent Publication (Kokai) No.10-87567), cephem derivatives (Japanese Unexamined Patent Publication(Kokai) No. 10-87493), isoxazole derivatives (Japanese Unexamined PatentPublication (Kokai) No. 11-1479), imidazolidine derivatives(WO96-04248), hydantoin derivatives (Japanese Unexamined PatentPublication (Kokai) No. 9-31061), quinazoline derivatives (WO97-11941),etc. have been reported, but no satisfactory medicament or treatmentmethod using inhibition of the activity of chymase as a strategy fortreatment has yet been established.

DISCLOSURE OF THE INVENTION

[0008] The object of the present invention is to provide a sideeffect-free, safe medicament for prevention or treatment of fibrosis ofthe skin or various organs, which suppresses the progression of thedisease, prevents the progression of complications, and improves thequality of life of the patient.

[0009] The present inventors engaged in intensive studies to achievethis object focusing on subcutaneous fibrous layer hypertrophy involvingthe dysbolism of connective tissue protein and, as a result, found thata chymase inhibitor alleviates the dysbolism of collagen and suppressesthe increase in the subcutaneous fibrous layer and thereby completed thepresent invention.

[0010] That is, in accordance with the present invention, there isprovided a medicament for the prevention or treatment of fibrosisinvolving extracellular matrix dysbolism having a chymase inhibitor asan effective ingredient.

[0011] In accordance with the present invention, there is also provideda pharmaceutical composition for the prevention or treatment of fibrosisinvolving extracellular matrix dysbolism including an amount of achymase inhibitor for alleviating extracellular matrix dysbolism and apharmaceutically acceptable vehicle.

[0012] In accordance with the present invention, the present inventionfurther provides a medicament for alleviating extracellular matrixdysbolism having a chymase inhibitor as an effective ingredient.

BRIEF DESCRIPTION OF THE DRAWINGS

[0013]FIG. 1 is a graph showing the effects of a chymase inhibitor(Compound 18) on chymase activity in various tissues in mice in Example2.

[0014]FIG. 2 is a graph showing the results of measurement of thecontent of skin collagen (hydroxyproline content) in Tsk mice in Example3.

[0015]FIG. 3 is a graph showing the results of measurement of the degreeof the thickness of subcutaneous fibrous layer in Tsk mice in Example 3.

[0016]FIG. 4 is a graph showing the results of measurement of the mastcell density in the skin of Tsk mice in Example 3.

[0017]FIG. 5 is a graph showing the results of measurement of chymaseactivity in the skin of Tsk mice in Example 3.

[0018]FIG. 6 is a graph showing the results of measurement of the mRNAcontent for the skin chymase of Tsk mice in Example 3.

[0019]FIG. 7 is a graph showing the results of measurement of thethickness of subcutaneous fibrous layer in Tsk mice in Example 4.

[0020]FIG. 8 is a graph showing the results of measurement of thechymase activity in the skin of Tsk mice in Example 4.

[0021]FIG. 9 is a graph showing the change of skin collagen content(hydroxyproline content) in the lung in bleomycin-induced pulmonaryfibrosis model in mice. * and ** respectively indicate that P value ofdetermination of significant difference (Dunnett's test) when comparedwith a control group (amount of administration of bleomycin of 0) issmaller than 0.05 and 0.01.

[0022]FIG. 10 is a graph showing the results of measurement of thechymase activity in the lung of bleomycin-induced mice. * indicates thatP value of determination of significant difference (Student's t-test),when compared with normal mice, is smaller than 0.05.

[0023]FIG. 11 is a graph showing the effect of chymase inhibitor on thecontent of skin collagen (hydroxyproline content) in the lung of ableomycin-induced mice pulmonary fibrosis model. # indicates that Pvalue of determination of significant difference (Student's t-test),when compared with a group administered saline, is smaller than 0.01,while * indicates that P-value of determination of significantdifference (Dunnett's test), when compared with a group administeredHPC/saline, is smaller than 0.05.

BEST MODE FOR CARRYING OUT THE INVENTION

[0024] In this specification, the fibrosis involving extracellularmatrix dysbolism includes diseases whose onset is caused by theoccurrence of extracellular matrix dysbolism, diseases whose conditionsare aggravated by the occurrence of extracellular matrix dysbolism, anddiseases whose cure is delayed by the occurrence of extracellular matrixdysbolism. For example, these diseases include scleroderma, pulmonaryfibrosis, benign prostatomegaly, myocardial fibrogenesis followingmyocardial infarction, myocardial fibrosis, musculoskeletal fibrosis,post-surgical adhesion, hypertropic scars and keloids, cirrhosis,hepatic fibrosis, renal fibrosis, fibrous vascular disorders, andcomplications of diabetes such as retinitis due to fibrousmicrovasculitis, neurosis, nephropathy, and peripheral arteritis or acondition related to the same.

[0025] The chymase inhibitor able to be used in the present inventioncan be selected as a substance inhibiting chymase activity by the use ofmethods workable by persons skilled in the art. As the method ofselection, for example, the method of the later explained Example 1 maybe used. The compounds obtained in this way include known compoundspreviously reported as chymase inhibitors, for example, the lowmolecular weight chymase inhibitors such as shown in the book (ProteaseInhibitors; Barrett et al., Eds; Elssevier Science B. V.; Amsterdam,1996), a-keto acid derivatives reported as peptide type inhibitors(WO93-25574, Proc. Natl. Acad. Sci. USA, 1995, 92, 6738),α,α-difluoro-β-keto acid derivatives (Japanese Unexamined PatentPublication (Kokai) No. 9-124691), tripeptide inhibitors (WO93-03625),phosphoric acid derivatives (Oleksyszyn et al., Biochemistry 30, 485,1991), peptide like inhibitors such as trifluoromethylketone derivatives(WO96-33974, Japanese Unexamined Patent Publication (Kokai) No.10-53579) and acetoamide derivatives (Japanese Unexamined PatentPublication (Kokai) No. 10-7661, Japanese Unexamined Patent Publication(Kokai) No. 10-53579, Japanese Unexamined Patent Publication (Kokai) No.11-246437, WO99-41277, WO98-18794, WO96-39373), non-peptide typeinhibitors such as triazine derivatives (Japanese Unexamined PatentPublication (Kokai) No. 8-208654 and Japanese Unexamined PatentPublication (Kokai) No. 10-245384), phenol ester derivatives (JapaneseUnexamined Patent Publication (Kokai) No. 10-87567), cephem derivatives(Japanese Unexamined Patent Publication (Kokai) No. 10-87493), isoxazolederivatives (Japanese Unexamined Patent Publication (Kokai) No.11-1479), imidazolidine derivatives (WO96-04248), hydantoin derivatives(Japanese Unexamined Patent Publication (Kokai) No. 9-31061),quinazoline derivatives (WO97-11941), etc., but as a representativeexample of a preferable chymase inhibitor, a compound of the followingformula (I) and its pharmaceutically acceptable salts may be mentioned.

[0026] wherein, the ring A represents an aryl group;

[0027] R¹ represents a hydroxyl group, an amino group, a C₁ to C₄ loweralkylamino group which may be substituted with a carboxylic acid group,a C₇ to C₁₀ lower aralkylamino group which may be substituted with acarboxylic acid group, an amino group acylated with a C₁ to C₄ loweraliphatic acid which may be substituted with a carboxylic acid group, anamino group acylated with an aromatic ring carboxylic acid which may besubstituted with a carboxylic acid group, an amino group acylated with aheteroaromatic ring carboxylic acid which may be substituted with acarboxylic acid group, an amino group sulfonylated with a C₁ to C₄ loweralkanesulfonic acid which may be substituted with a carboxylic acidgroup, an amino group sulfonylated with an aromatic ring sulfonic acidwhich may be substituted with a carboxylic acid group, an amino groupsulfonylated with a heteroaromatic ring sulfonic acid which may besubstituted with a carboxylic acid group, a C₁ to C₄ lower alkyl groupsubstituted with a carboxylic acid group, or a C₂ to C₄ lower alkylenegroup which may be substituted with a carboxylic acid group;

[0028] R² and R3 may be the same or different and represent a hydrogenatom, an unsubstituted or substituted C₁ to C₄ lower alkyl group, ahalogen atom, a hydroxyl group, a C₁ to C₄ lower alkoxyl group, an aminogroup, an unsubstituted or substituted C₁ to C₄ lower alkylamino group,an unsubstituted or substituted C₇ to C₁₀ aralkylamino group, an aminogroup acylated with a C₁ to C₄ lower aliphatic acid which may besubstituted with a carboxylic acid group, an amino group acylated withan aromatic ring carboxylic acid which may be substituted with acarboxylic acid group, an amino group acylated with a heteroaromaticring carboxylic acid which may be substituted with a carboxylic acidgroup, an amino group sulfonylated with a C₁ to C₄ lower alkanesulfonicacid which may be substituted with a carboxylic acid group, an aminogroup sulfonylated with an aromatic ring sulfonic acid which may besubstituted with a carboxylic acid group, an amino group sulfonylatedwith a heteroaromatic ring sulfonic acid which may be substituted with acarboxylic acid group, or a carboxylic acid group or

[0029] when the ring A is a benzene ring, R¹ and R² may form, togetherwith the substituting benzene ring, a fused heterocyclic ring which maybe substituted with a carboxylic acid and in which the carbon atom inthe ring may form a carbonyl group and R³ is the same as defined above;and

[0030] X represents a hydrogen atom, a C₁ to C₄ lower alkyl group, a C₁to C₄ lower alkoxy group, a halogen atom, a hydroxyl group, an aminogroup, or a nitro group.

[0031] In the general formula (I), preferable examples of the aryl grouprepresented by the ring A are a benzene ring and a naphthalene ring.

[0032] Preferable examples of the C₁ to C₄ lower alkylamino group whichmay be substituted with the carboxylic acid group and the C₇ to C12lower aralkylamino group which may be substituted with a carboxylic acidgroup represented by R¹ are a methylamino group, an ethylamino group, apropylamino group, a butylamino group, a carboxymethylamino group, acarboxyethylamino group, a carboxypropylamino group, a carboxybutylaminogroup, a benzylamino group, a phenetylamino group, a phenylpropylaminogroup, a phenylbutylamino group, a carboxybenzylamino group, acarboxyphenetylamino group, a carboxyphenylpropylamino group, acarboxyphenylbutylamino group, etc.

[0033] Preferable examples of the amino group acylated with a C₁ to C₄lower aliphatic acid which may be substituted with a carboxylic acidgroup, the amino group acylated with an aromatic ring carboxylic acidwhich may be substituted with a carboxylic acid group, and the aminogroup acylated with a heteroaromatic ring carboxylic acid which may besubstituted with a carboxylic acid group represented by R¹ are aformylamino group, an acetylamino group, a propionylamino group, abutyrylamino group, a benzoylamino group, a naphthoylamino group, apyridinecarbonylamino group, a pyrrolecarbonylamino group, acarboxyacetylamino group, a carboxypropionylamino group, acarboxybutyrylamino group, a carboxybenzoylamino group, acarboxynaphthoylamino group, a carboxypyridinecarbonylamino group, acarboxypyrrolecarbonylamino group, etc.

[0034] Preferable examples of the amino group sulfonylated with a C₁ toC₄ lower alkanesulfonic acid which may be substituted with a carboxylicacid group, the amino group sulfonylated with an aromatic ring sulfonicacid which may be substituted with a carboxylic acid group, and theamino group sulfonylated with a heteroaromatic ring sulfonic acid whichmay be substituted with a carboxylic acid group represented by R¹ are amethanesulfonylamino group, an ethanesulfonylamino group, apropanesulfonylamino group, a butanesulfonylamino group, abenzenesulfonylamino group, a naphthalenesulfonylamino group, apyridinesulfonylamino group, a pyrrolesulfonylamino group, acarboxymethanesulfonylamino group, a carboxyethanesulfonylamino group, acarboxypropanesulfonylamino group, a carboxybutane-sulfonylamino group,a carboxybenzenesulfonylamino group, a carboxynaphthalenesulfonylaminogroup, a carboxypyridinesulfonylamino group, acarboxypyrrolesulfonylamino group, etc.

[0035] Preferable, examples of the C₁ to C₄ lower alkyl groupsubstituted with a carboxylic acid group represented by R¹ are an aceticacid group, a propionic acid group, a butyric acid group, a valeric acidgroup, etc.

[0036] Preferable examples of the C₂ to C₄ lower alkylene groupsubstituted with a carboxylic acid group represented by R¹ are anacrylic acid group, a crotonic acid group, etc.

[0037] Preferable examples of the unsubstituted or substituted C₁ to C₄lower alkyl group represented by R² or R³ are a straight-chain alkylgroup such as a methyl group, an ethyl group, a n-propyl group, and an-butyl group and a branched alkyl group such as an isopropyl group, asec-butyl group, and a t-butyl group.

[0038] Preferable examples of the substituent group of the C₁ to C₄lower alkyl group are a carboxylic acid group, a halogen atom such as afluorine atom and a chlorine atom, a C₁ to C₄ lower alkoxy group, anamino group, a methylamino group, a dimethylamino group, acarboxymethylamino group, a carboxyethylamino group, etc.

[0039] Preferable examples of the halogen atom represented by R² or R³are a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

[0040] Preferable examples of the C₁ to C₄ lower alkoxyl grouprepresented by R² or R³ are a straight-chain alkyloxy group such as amethoxy group, an ethoxy group, a n-propyloxy group, and a n-butoxygroup and a branched alkyloxy group such as an isopropyloxy group, asec-butoxy group, and a t-butoxy group.

[0041] Preferable examples of the unsubstituted or substituted C₁ to C₄lower alkylamino group represented by R² or R³ are a methylamino group,an ethylamino group, a propylamino group, a butylamino group, etc.

[0042] Preferable examples of the substituent group of the C₁ to C₄lower alkylamino group are a carboxylic acid group, a halogen atom suchas a fluorine atom and a chlorine atom, a C₁ to C₄ lower alkoxyl group,etc.

[0043] Preferable examples of the unsubstituted or substituted C₇ to C₁₂lower aralkylamino group represented by R² or R³ are a benzylaminogroup, a phenetylamino group, a phenylpropylamino group, aphenylbutylamino group, etc.

[0044] Preferable examples of the substituent group of the aralkylaminogroup are a carboxylic acid group, a halogen atom such as a fluorineatom and a chlorine atom, a C₁ to C₄ lower alkoxyl group, etc.

[0045] Preferable examples of the amino group acylated with a C₁ to C₄lower aliphatic acid which may be substituted with a carboxylic acidgroup, the amino group acylated with an aromatic ring carboxylic acidwhich may be substituted with a carboxylic acid group, and the aminogroup acylated with a heteroaromatic ring carboxylic acid which may besubstituted with a carboxylic acid group represented by R² or R³ are aformylamino group, an acetylamino group, a propionylamino group, abutyrylamino group, a benzoylamino group, a naphthoylamino group, apyridinecarbonylamino group, a pyrrolecarbonylamino group, acarboxyacetylamino group, a carboxypropionylamino group, acarboxybutyrylamino group, a carboxybenzoylamino group, acarboxynaphthoylamino group, a carboxypyridinecarbonylamino group, acarboxypyrrolecarbonylamino group, etc.

[0046] Preferable examples of the amino group sulfonylated with a C₁ toC₄ lower alkanesulfonic acid which may be substituted with a carboxylicacid group, the amino group sulfonylated with an aromatic ring sulfonicacid which may be substituted with a carboxylic acid group, and theamino group sulfonylated with a heteroaromatic ring sulfonic acid whichmay be substituted with a carboxylic acid group represented by R² or R³are a methanesulfonylamino group, an ethanesulfonylamino group, apropanesulfonylamino group, a benzenesulfonylamino group, anaphthalenesulfonylamino group, a pyridinesulfonylamino group, apyrrolesulfonylamino group, a carboxymethanesulfonylamino group, acarboxyethanesulfonylamino group, a carboxypropanesulfonylamino group, acarboxybenzenesulfonylamino group, a carboxynaphthalenesulfonylaminogroup, a carboxypyridine-sulfonylamino group, acarboxypyrrolesulfonylamino group, etc.

[0047] Preferable examples of the fused heterocyclic ring which may besubstituted with a carboxylic acid and in which the carbon atom in thering may form a carbonyl group which R¹ and R² form together with thesubstituting benzene ring when the ring A is a benzene ring, are atetrahydroquinoline ring and a benzoxazine ring, for example, atetrahydroquinoline, a benzoxazine, a quinoxaline, a benzodioxane, acarboxytetrahydroquinoline, a carboxybenzoxazine, a carboxyquinoxaline,a carboxybenzodioxane, etc.

[0048] Preferable examples of the C₁ to C₄ lower alkyl group representedby X are a straight-chain alkyl group such as a methyl group, an ethylgroup, a n-propyl group, and a n-butyl group and a branched alkyl groupsuch as an isopropyl group, a sec-butyl group, and a t-butyl group.

[0049] Preferable examples of the C₁ to C₄ lower alkoxyl grouprepresented by X are a straight-chain alkyloxy group such as a methoxygroup, an ethoxy group, a n-propyloxy group, and a n-butoxy group and abranched alkyloxy group such as an isopropyloxy group, a sec-butoxygroup, and a t-butoxy group.

[0050] Preferable examples of the halogen atom represented by X, are afluorine atom, a chlorine atom, a bromine atom and an iodine atom.

[0051] Further, examples of a pharmaceutically acceptable salts are anacid salt such as a hydrochloric acid salt, a methanesulfonic acid salt,and a trifluoroacetic acid salt and an alkali metal salt such as asodium salt and a potassium salt.

[0052] The quinazoline derivative having the formula (I) according tothe present invention may, for example, be synthesized by the followingSynthesis Method (A) or (B).

[0053] Synthesis Method (A)

[0054] A compound having the formula (I-1):

[0055] wherein the ring A is the same as defined above and R¹, R² and R³represent R¹, R² and R³, which may be protected with a protecting group,respectively, and R¹, R² and R³ represent the same as defined above

[0056] is reacted with an anthranilic acid derivative having the formula(I-2):

[0057] wherein X represents X, which may be protected with a protectinggroup, and X represents the same as defined above

[0058] using the method described, for example, in JP-A-6-199839 toobtain a sulfonylurea derivative having the formula (I-3):

[0059] wherein the ring A, R¹, R², R³ and X represent the same asdefined above,

[0060] then, a condensing agent for example, 1,1-carbonyldiimidazole(hereinafter referred to as CDI) is used to obtain the quinazoline ring,and if necessary, the protecting groups of R¹, R², R³ and X aredeprotected.

[0061] In this reaction, when R¹, R² or R³ represents a group containinga hydroxyl group, an amino group, or a carboxylic acid group, R¹, R² orR³ may be optionally protected by a protecting group such as abenzyloxycarbonyl group, a t-butoxycarbonyl group, a benzyl group, anallyl group, a t-butyl group, etc. When X represents a hydroxyl group oran amino group, X may be optionally protected with a protecting groupsuch as a benzyloxycarbonyl group, a t-butoxycarbonyl group, a benzylgroup, an allyl group, a t-butyl group, etc.

[0062] The compound having the formula (I-1) used in this reactionincludes a commercially available or known compound or a compound whichcan be synthesized by a known method may be used. For example, using thesynthesis method described in the specification of European Patent No.0269141, it is possible to use a compound which can be synthesized fromthe corresponding sulfonamide derivative using chlorosulfonylisocyanate. For example, it is possible to use3-allyloxycarbonyl-methylbenzenesulfonyl isocyanate,4-allyloxycarbonyl-methylbenzenesulfonyl isocyanate,4-allyloxybenzenesulfonyl isocyanate, etc.

[0063] As the anthranilic acid derivative having the formula (1-2) usedfor this reaction, a commercially available or known compound or acompound which can be synthesized by a known method may be used. Forexample, anthranilic acid, 4-chloroanthranilic acid,4-methoxyanthranilic acid, 5-chloroanthranilic acid,4-hydroxyanthranilic acid, etc. may be used.

[0064] The reaction to obtain the quinazoline ring from the sulfonylureaderivative having the formula (I-3) may be carried out using anaprotonic solvent such as, for example, an ether solvent such astetrahydrofuran and dioxane, a halogen-containing solvent such asmethylene chloride, or dimethylformamide etc. at a temperature of −50°C. to 50° C., preferably −20° C. to room temperature. Further, for thecyclization reaction, it is possible to use an ordinary condensing agentwhich includes, for example, CDI, dicyclohexylcarbodiimide, and similarcarbodiimide compounds, mixed anhydrides, etc. The deprotecting reactioncan be carried out by an ordinary method using hydrolysis with an acidor alkali, reduction or oxidation etc.

[0065] Synthesis Method (B)

[0066] A compound having the formula (I-4):

[0067] wherein the ring A, R¹, R² and R³ represent the same as definedabove

[0068] is condensed with an anthranilic acid derivative having theformula (I-5):

[0069] wherein X represents the same as defined above, Ph represents aphenyl group, and R⁴ represents a protecting group of the carboxylgroup, which is specifically a group capable of being released byhydrolysis or hydrogenolysis, such as, for example, a methyl group, anethyl group, or a benzyl group using, for example,1,8-diazabicyclo[5,4,0]-7-undecene (hereinafter referred to as DBU) toform a sulfonylurea derivative having the formula (I-6):

[0070] wherein the ring A, R¹, R², R³, R⁴ and X are the same as definedabove,

[0071] which is then hydrolyzed with an alkali or hydrogenolyzed toderive a corresponding carboxylic acid represented by the formula (I-3),then the quinazoline ring is obtained and optionally the protectinggroups of R¹, R², R³ and X are deprotected, in the same way as inSynthesis Method (A). In this reaction, when R¹, R² or R³ represents agroup containing a hydroxyl group, an amino group, or a carboxylic acidgroup, R¹, R² or R³ may be optionally protected by a protecting groupsuch as a benzyloxycarbonyl group, a t-butoxycarbonyl group, a benzylgroup, an allyl group, a t-butyl group, etc. When X represents ahydroxyl group or an amino group, X may be optionally protected with aprotecting group such as a benzyloxycarbonyl group, a t-butoxycarbonylgroup, a benzyl group, an allyl group, a t-butyl group, etc.

[0072] As the compound having the formula (I-4) used in the reaction, acommercially available or known compound or a compound which can besynthesized by a known method may be used. For example,3-hydroxybenzenesulfonamide, 2-aminobenzenesulfonamide,3-aminobenzenesulfonamide, 4-aminobenzenesulfonamide,(±)-2-(4-aminosulfonylphenyl)butyric acid,3-benzyloxycarbonylamino-4-chlorobenzenesulfonamide,4-benzyloxycarbonylamino-3-chlorobenzenesulfonamide,4-amino-3,5-dichlorobenzenesulfonamide,3-benzyloxycarbonylamino-4-methylbenzenesulfonamide,4-t-butoxycarbonyl-3-hydroxybenzenesulfonamide,3-benzyloxycarbonylamino-4-t-butoxycarbonylbenzenesulfonamide,4-t-butoxycarbonyl-3-hydroxybenzenesulfonamide,3-t-butoxycarbonyl-4-hydroxybenzenesulfonamide,3-acetamide-4-methoxybenzenesulfonamide,3-(3-aminosulfonyl)phenylacrylic acid t-butylester,3-amino-4-methoxybenzenesulfonamide,4-methoxy-3-methylsulfonylaminobenzenesulfonamide,3-carboxy-4-hydroxy-2-naphthalenesulfonamide,4-benzyloxycarbonylamino-3-t-butoxycarbonylbenzenesulfonamide,(±)-3-t-butoxycarbonyl-2-oxo-1H,3H-quinoline-7-sulfonamide,(±)-2-t-butoxycarbonyl-3-oxo-1,4-benzoxazine-6-sulfonamide, etc. may beused.

[0073] As the anthranilic acid derivative having the formula (I-5) usedin this reaction, a commercially available or known compound or acompound which can be synthesized by a known method may be used. Forexample, methyl 4-chloro-2-N-phenoxycarbonylanthranilate, ethyl4-chloro-2-N-phenoxycarbonylanthranilate, benzyl4-chloro-2-N-phenoxycarbonylanthranilate, methyl5-chloro-2-N-phenoxycarbonylanthranilate, ethyl5-chloro-2-N-phenoxycarbonylanthranilate, benzyl5-chloro-2-N-phenoxycarbonylanthranilate, methyl4-methoxy-2-N-phenoxycarbonylanthranilate, ethyl4-methoxy-2-N-phenoxycarbonylanthranilate, benzyl4-methoxy-2-N-phenoxycarbonylanthranilate, methyl4-hydroxy-2-N-phenoxycarbonylanthranilate, ethyl4-hydroxy-2-N-phenoxycarbonylanthranilate, benzyl4-hydroxy-2-N-phenoxycarbonylanthranilate, etc. may be used.

[0074] The reaction for obtaining the compound having the formula (I-4)and the anthranilic acid derivative having the formula (I-5) condense toobtain a sulfonylurea derivative having the formula (I-6), may becarried out using an aprotic solvent, for example, an ether solvent suchas tetrahydrofuran or dioxane, a halogen-containing solvent such asmethylene chloride, or dimethylformamide etc. at a temperature of −50°C. to 50° C., preferably −20° C. to room temperature. Further, as theusable for the condensation reaction, an organic strong base such asDBU, inorganic bases such as potassium carbonate, sodium carbonate,potassium hydroxide, and sodium hydroxide, or metal bases such as sodiumhydride may be used.

[0075] In the reaction for alkali hydrolysis or hydrogenolysis of thesulfonylurea derivative having the formula (I-6) thus obtained to obtainthe sulfonylurea derivative having the formula (I-3), ordinaryhydrolysis conditions or hydrogenolysis conditions for esters may beused.

[0076] Note that the above reaction may be carried out while protectingthe functional groups not involved in the reaction. According to thetype of the protecting group, the protection is removed by chemicalreduction or other ordinary protection-removing reactions. For example,when the protecting group is a t-butyl group or t-butoxycarbonyl group,trifluoroacetic acid may be used, while when it is an allyl group,palladium catalysts such as tetrakis(triphenylphosphine)palladium (0)may be used.

[0077] The compound having the formula (I), wherein R¹ represents anamino group acylated with a C₁ to C₄ lower aliphatic acid which may besubstituted with a carboxylic acid, an amino group acylated with anaromatic ring carboxylic acid which may be substituted with a carboxylicacid and an amino group acylated with an heteroaromatic ring carboxylicacid which may be substituted with a carboxylic acid, can be obtainedfrom the compound having the formula (I), wherein R¹ represents an aminogroup, by acylating the same with carboxylic acid, carboxylic acidchloride, carboxylic acid anhydride using an ordinary method.

[0078] The compound having the formula (I), wherein R¹ represents anamino group sulfonylated with a C₁ to C₄ lower alkane sulfonic acidwhich may be substituted with a carboxylic acid, an amino groupsulfonylated with an aromatic ring sulfonic acid which may besubstituted with a carboxylic acid and an amino group sulfonylated withan heteroaromatic ring sulfonic acid which may be substituted with acarboxylic acid, can be obtained from the compound having the formula(I), wherein R¹ represents an amino group, by sulfonylating the samewith sulfonic acid or sulfonic acid chloride using an ordinary method.

[0079] The product obtained according to the above-mentioned processescan be purified by a method such as recrystallization or columnchromatography.

[0080] If necessary, the compounds having the formula (I) of the presentinvention obtained according to the above-mentioned processes can eachbe reacted with one of various acids or basis to convert the compoundinto their salt. Exemplary acids usable for the conversion of thecompound having the formula (I) into their salts can include inorganicacids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuricacid, phosphoric acid; and organic acids such as methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid,citric acid, lactic acid, maleic acid, fumaric acid, tartaric acid,acetic acid, adipic acid, palmitic acid and tannic acid. Exemplaryusable basis for the conversion of the compound having the formula (I)into their salts can include sodium hydroxide, lithium hydroxide andpotassium hydroxide.

[0081] Further, the compounds having the formula (I) according to thepresent invention include those containing asymmetric centers. Eachracemic mixture can be isolated by one or more of various methods,whereby a single optically-active substance can be obtained. Usablemethods include, for example:

[0082] (1) Isolation by optically active column.

[0083] (2) Isolation by recrystallization subsequent to conversion intoa salt with an optically active acid or base.

[0084] (3) Isolation by a combination of the above methods (1) and (2).

[0085] These compounds can be evaluated according to the method ofExample 4 or 7 below, with respect to the improvement in the abnormalexacerbation.

[0086] To use the effective ingredient of the present invention as amedicament for the prevention or treatment of fibrosis involvingextracellular matrix dysbolism, a pharmaceutical composition for theprevention or treatment of fibrosis involving extra cellular matrixdysbolism, and a medicament for alleviation of extracellular matrixdysbolism, one or more of the compounds of the present invention may bemixed and formed into a form suitable for use in the method ofadministration by an ordinary method. Examples of preparation forms fororal administration include capsules, tablets, granules, fine granules,syrups, dry syrups, and other preparations, while examples ofpreparation forms for non-oral administration include injections andbesides suppositories such as rectal suppositories and vaginalsuppositories, transnasal preparations such as sprays and ointments, andpercutaneous preparations such as tapes for percutaneous absorption.

[0087] The clinical dose of the compound according to the presentinvention varies according to the diseased condition, degree ofseriousness, age, presence of complications, etc. and also variesaccording to its preparation form. In the case of oral administration,however, it may be dosed usually, in terms of effective ingredients, as1 to 1000 mg per adult per day. In the case of non-oral administration,it is sufficient to administer {fraction (1/10)} to ½ the amount of thecase of oral administration. These dosages can be suitably adjustedaccording to the age, the diseased condition, and the like of thepatient to be dosed.

[0088] In the present invention, the chymase inhibitor can beadministered alone as it is without being mixed with another effectiveingredient, but considering the disease in question, the symptoms,complications, etc., it may also administered as a medicinal preparationcontaining other effective ingredients. Further, it may also be combinedwith these other effective ingredients. The amounts of the othereffective ingredients used are not particularly limited, but aredetermined considering the minimum amounts for expression of theireffects alone, the occurrence of side effects, etc.

[0089] In treatment, the form of preparation and the method of combinedtreatment including preparations containing the chymase inhibitor aloneas an effective ingredient and preparations also containing othereffective ingredients are suitably selected by a physician in accordancewith the age of the patient, the symptoms, etc.

[0090] The toxicity of the compound according to the present inventionis low. The acute toxicity values LD₅₀ at 24 hours after oraladministration to 5-week old male mice were 1 g/kg or more.

EXAMPLES

[0091] The present invention will now be further explained by, but is byno means limited to, the following Examples, but the scope of theinvention is not limited to these Examples needless to say.

[0092] To demonstrate the usefulness of the chymase inhibitor againstfibrosis, the test results obtained by using Tsk mice, as the model ofsclerodermatous mice, and bleomycin-induced mice fibrosis in lung, asthe model of fibrosis, are provided below.

Preparation Example 1 Synthesis of7-Chloro-3-(3-Hydroxvbenzenesulfonyl)-2,4(1H,3H)-Quinazolinedione(Compound 1)

[0093] Following the Synthesis Method (B), 938 mg (5.42 mmol) of3-hydroxybenzenesulfonamide was dissolved in 40 ml of tetrahydrofuran,then 892 μl (5.96 mmol) of 1,8-diazabicyclo[5,4,0]-7-undecene(hereinafter referred to as DBU) was added dropwise. The reactionsolution was stirred at room temperature for 15 minutes, then 1.66 g(5.42 mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilate was addedand the mixture was stirred at room temperature overnight. An excessamount of water was poured into the reaction solution, then the mixturewas made acidic with hydrochloric acid and extracted with ethyl acetate.The organic layer was washed with water and saturated saline, dried overanhydrous magnesium sulfate, and concentrated. The crude product thusobtained was purified by silica gel column chromatography (0% to 5%methanol/dichloromethane) to obtain 1.23 g (yield 59%) of methyl4-chloro-2-{[(3-hydroxybenzenesulfonylamino)carbonyl]amino} benzoate.Properties: colorless amorphous, PMR (δ ppm, DMSO-d₆): 3.91 (3H, s),7.02 (1H, m), 7.09 (1H, m), 7.34 (1H, t), 7.57 (2H, m), 7.89 (1H, d),8.38 (1H, d), 10.94 (1H, s). Next, the 1.23 g (3.2 mmol) of the compoundthus obtained was dissolved in 20 ml of methanol, then 10 ml of 2Nsodium hydroxide aqueous solution was added dropwise. The reactionsolution was stirred at room temperature for 15 minutes, then an excessamount of water was added and the mixture was made acidic withhydrochloric acid. This was then stirred to cause crystals toprecipitate which were then obtained by filtration and dried to obtaincarboxylic acid. The product thus obtained was dissolved in 50 ml oftetrahydrofuran (hereinafter referred to as THF), then 434 mg (2.68mmol) of CDI was added under ice cooling and the mixture was stirred for30 minutes. The reaction solution was diluted with ethyl acetate, washedwith water and saturated saline, and dried over anhydrous magnesiumsulfate, then concentrated to obtain a crude product. The crude productwas purified by silica gel column chromatography (ethylacetate:n-hexane=1:2) to obtain 230 mg (yield 20%: 2 steps) of theabove-identified compound. Properties: colorless crystal, Meltingpoint: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 7.12 (2H, s),7.24 (1H, d), 7.48 (1H, t), 7.58 (2H, s), 7.85 (1H, d), 10.28 (1H, S),11.63 (1H, s).

Preparation Example 2 Synthesis of3-(2-Aminobenzenesulfonyl)-7-Chloro-2,4(1H,3H)-Quinazolinedione(Compound 2)

[0094] 2.7 g (15.7 mmol) of 2-aminobenzenesulfonamide and 4.8 g (15.7mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated inthe same way as Preparation Example 1 to obtain 3.2 g (yield 58%: 3steps) of the above-identified compound. Properties: colorless crystal,Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 6.46 (2H,s), 6.65 (1H, t), 6.81 (1H, d), 7.12 (1H, s), 7.23 (1H, d), 7.34 (1H,t), 7.76 (1H, d), 7.86 (1H, d).

Preparation Example 3 Synthesis of7-Chloro-3-(2-Methylsulfonylaminobenzenesulfonyl-2.4(1H,3H)-Quinazolinedione(Compound 3)

[0095] 22 mg (0.06 mmol) of Compound 2 was dissolved in 200 Al ofpyridine, 11.6 μl (0.15 mmol) of methanesulfonyl chloride was addeddropwise, then the resultant mixture was stirred at room temperatureovernight. An excess amount of water was added to the reaction solutionand the mixture was extracted with ethyl acetate. The organic layer waswashed with 1N aqueous hydrochloric acid solution and saturated saline,then dried over anhydrous magnesium sulfate and concentrated to obtain acrude product. The crude product was crystallized from diethyl ether toobtain 16 mg (0.04 mmol) of the above-identified compound. Properties:colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm,DMSO-d₆): 3.61 (3H, s), 7.10 (1H, d), 7.20 (1H, d), 7.74 (1H, d),7.82-7.90 (4H, m), 8.34 (1H, d), 11.70 (1H, s).

Preparation Example 4 Synthesis of3-(4-Aminobenzenesulfonyl)-7-Chloro-2,4(1H,3H)-Quinazolinedione(Compound 4)

[0096] 2.7 g (15.7 mmol) of 4-aminobenzenesulfonamide and 4.8 g (15.7mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated inthe same way as Preparation Example 1 to obtain 7.9 g (yield 94%) ofmethyl2-{[(4-aminobenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate.Properties: colorless amorphous, PMR (δ ppm, DMSO-d₆): 3.59 (3H, s),5.37 (2H, s), 6.45 (2H, d), 6.83 (1H, dd), 7.41 (2H, d), 7.81 (1H, d),8.66 (1H, d), 9.64 (1H,'s).

[0097] Then, from the resultant 7.9 g (14.8 mmol) of sulfonylureaproduct, in the same way, 4.3 g (yield 83%: 2 steps) of theabove-identified compound was obtained. Properties: colorless crystal,Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 6.39 (2H,s), 6.63 (2H, d), 7.09 (1H, s), 7.22 (1H, d), 7.76 (2H, d), 7.83 (1H,d), 11.51 (1H, s).

Preparation Example 5 Synthesis of3-(3-Carboxymethyl-Benzenesulfonyl)-7-Chloro-2.4(1H,3H)-Quinazolinedione(Compound 5)

[0098] Following the Synthesis Method (A), 3.27 g (11.6 mmol) of3-allyloxycarbonylmethylbenzenesulfonyl isocyanate was dissolved in 100ml of anhydrous THF, then 1.98 g (11.5 mmol) of 4-chloroanthranilic acidwas added and the mixture was stirred at room temperature for 2 hours.The reaction solution was cooled with ice water, then 1.87 g (11.5 mmol)of CDI was added and the resultant mixture was stirred under ice coolingfor 30 minutes. An excess amount of water was poured into the reactionsolution, then the mixture was extracted with ethyl acetate. The organiclayer was washed, dried, and concentrated to obtain a crude product.This was crystallized with a small amount of ethyl acetate to obtain 2.0g (yield 40%) of3-(3-allyloxy-carbonylmethylbenzenesulfonyl)-7-chloro-2,4(1H,3H)-quinazolinedione.The allyl product thus obtained was dissolved in 100 ml of a formicacid-THF (1:9) mixture and 700 mg of triphenylphosphine was added. Thereactor was shaded from light and under nitrogen atmosphere, then 700 mgof tetrakis(triphenylphosphine)palladium (0) was added and the resultantmixture was stirred while shaded at room temperature overnight. Thereaction solution was concentrated in vacuo and the solid obtained waswashed with methylene chloride to obtain 1.47 g (yield 81%) of theabove-identified compound. Properties: colorless crystal, Meltingpoint: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 3.76 (2H, s),7.13 (1H, s), 7.24 (1H, d), 7.61-7.69 (2H, m), 7.86 (1H, d), 8.05 (2H,s), 12.50 (1H, br).

Preparation Example 6 Synthesis of3-(4-Carboxvmethyl-benzenesulfonyl)-7-Chloro-2.4(1H,3H)-Quinazolinedione(Compound 6)

[0099] 1.10 g (3.95 mmol) of 4-allyloxycarbonylmethyl-benzenesulfonylisocyanate and 678 mg (3.95 mmol) of 4-chloroanthranilic acid weretreated in the same way as in Preparation Example 5 to obtain 657 mg(yield 38%) of3-(4-allyloxycarbonylbenzenesulfonyl)-7-chloro-2,4(1H,3H)-quinazolinedione.538 mg (1.24 mmol) thereof was treated in the same way to obtain 342 mgof the above-identified compound (yield 70%). Properties: colorlesscrystal, Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆):3.75 (2H, s), 7.13 (1H, s), 7.23 (1H, d), 7.61-7.69 (2H, m), 7.86 (1H,d), 8.05 (2H, s), 12.07 (2H, br).

Preparation Example 7 Synthesis of(±)-2-{4-[(7-Chloro-2,4(1H,3H)-Quinazolin-3-yl)Sulfonyl]Phenyl}ButyricAcid (Compound 7)

[0100] 1.02 g (3.41 mmol) of t-butyl(±)-2-(4-amino-sulfonylphenyl)butyrate acid and 1.04 g (3.41 mmol) ofmethyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the sameway as Preparation Example 1 to obtain 1.46 g (yield 84%) of methyl2-[({4-[1-(t-butoxycarbonyl)propyl]benzenesulfonylamino}carbonyl)amino]-4-chlorobenzoate.Properties: colorless amorphous, PMR (δ ppm, CDCl₃): 0.89 (3H, t), 1.38(9H, s), 1.69-1.76 (1H, m), 2.03-2.10 (1H, m), 3.42 (lH, t), 3.94 (3H,S), 7.04 (1H, d), 7.47 (2H, d), 7.93 (1H, d), 8.01 (2H, d), 8.45 (1H,br), 11.04 (1H, br).

[0101] Next, 4.3 ml (8.6 mmol) of 2N sodium hydroxide aqueous solutionwas used to similarly form carboxylic acid in an amount of 1.43 g and463 mg (2.86 mmol) of CDI was used to obtain 970 mg (yield 71%: 2 steps)of t-butyl(±)-2-{4-[(7-chloro-2,4(1H,3H)-quinazolin-3-yl)sulfonyl]phenyl}butyrate.

[0102] Further, the t-butylester thus obtained was dissolved in 5 ml ofdichloromethane, then 5 ml of trifluoroacetic acid was added and theresultant mixture was stirred at room temperature for 40 minutes. Thereaction solution was concentrated in vacuo and the resultant crudeproduct was washed with a small amount of diethyl ether to obtain 820 mgof the above-identified compound (yield 96%). Properties: colorlesscrystal, Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆):0.84 (3H, t), 1.67-1.75 (1H, m), 1.98-2.05 (1H, m), 3.62 (1H, t), 7.11(1H, S), 7.24 (1H, d), 7.61 (2H, d), 7.86 (1H, d), 8.13 (2H, d), 11.62(1H, s).

Preparation Example 8 Synthesis of3-(3-Amino-4-Chlorobenzenesulfonyl)-7-Chloro-2,4(1H,3H)-Quinazolinedione(Compound 8)

[0103] 1.0 g (2.93 mmol) of3-benzyloxycarbonylamino-4-chlorobenzenesulfonamide and 1.18 g (2.93mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated inthe same way as Preparation Example 1 to obtain 1.43 g (yield 78%) ofbenzyl 2-{[(3-benzyloxycarbonylamino-4-chlorobenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate. Properties: colorlessamorphous, PMR (δ ppm, DMSO-d₆): 5.19 (2H, s), 5.36 (2H, s), 7.21 (1H,dd), 7.34-7.48 (10H, m), 7.72-7.76 (2H, m), 7.97 (1H, d), 8.25 (1H, d),8.30 (1H, d), 9.53 (1H, s), 10.30 (1H, S). 1.38 g (2.20 mmol) thereofwas dissolved in 50 ml of THF, then 200 mg of palladium-carbon (10%) wasadded and the mixture was stirred under a hydrogen flow for 2 hours. Thereaction mixture was filtered with Celite to remove thepalladium-carbon, then the filtrate was concentrated in vacuo to obtaina carboxylic acid. The product obtained was suspended in 50 ml of THF,then 356 mg (2.20 mmol) of CDI was added under ice cooling and theresultant mixture was treated in the same way as Preparation Example 1to obtain 560 mg (yield 66%: 2 steps) of the above-identified compound.Properties: colorless crystal, Melting point: >2000C (decomposition),PMR (δ ppm, DMSO-d₆): 6.00 (2H, s), 7.12 (1H, s), 7.26 (2H, t), 7.48(1H, d), 7.66 (1H, s), 7.86 (1H, d), 11.76 (1H, br).

Preparation Example 9 Synthesis of3-(4-Amino-3,5-Dichlorobenzenesulfonyl)-7-Chloro-2,4(1H,3H)-Quinazolinedione(Compound 9)

[0104] 1.06 g (4.40 mmol) of 4-amino-3,5-dichloro-benzenesulfonamide and1.34 g (4.40 mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilatewere treated in the same way as Preparation Example 1 to obtain 905 mg(yield 44%) of methyl2-{[(4-amino-3,5-dichlorobenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate.Properties: colorless amorphous, PMR (δ ppm, DMSO-d₆): 3.87 (3H, s),6.59 (2H, br), 7.22 (1H, dd), 7.72 (2H, s), 7.93 (1H, d), 8.24 (1H, d),10.17 (1H, S).

[0105] Then, from 905 mg (2.0 mmol) of the resultant sulfonylureaproduct, in the same way, 660 mg (yield 82%: 2 steps) of theabove-identified compound was obtained. Properties: colorless crystal,Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 6.80 (2H,s), 7.12 (1H, s), 7.24 (1H, d), 7.86 (1H, d), 7.92 (2H, s), 11.63 (1H,br).

Preparation Example 10 Synthesis of3-(3-Amino-4-Methylbenzenesulfonyl)-7-Chloro-2,4(1H,3H)-Quinazolinedione(Compound 10)

[0106] 960 mg (3.00 mmol) of3-benzyloxycarbonylamino-4-methylbenzenesulfonamide and 1.14 g (3.00mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated inthe same way as in Preparation Example 8 to obtain 1.14 g (yield 62% ofbenzyl2-{[(3-benzyloxycarbonylamino-4-methylbenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate.Properties: colorless amorphous, PMR (δ ppm, DMSO-d₆): 2.30 (3H, s),5.17 (2H, s), 5.36 (2H, s), 7.20 (1H, dd), 7.33-7.48 (11H, m), 7.63 (1H,d), 7.97 (1H, d), 8.11 (1H, s), 8.25 (1H, s), 9.27 (1H, s), 10.30 (1H,S), 12.20 (1H, br).

[0107] Then, from 1.14 g (1.87 mmol) of the resultant sulfonylureaproduct, in the same way, 190 mg (yield 27%: 2 steps) of theabove-identified compound was obtained. Properties: colorless crystal,Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 2.12 (3H,s), 5.47 (2H, s), 7.12 (1H, s), 7.16-7.25 (3H, m), 7.38 (1H, s), 7.85(1H, d), 11.58 (1H, s).

Preparation Example 11 Synthesis of3-[(3-Carboxymethylaminophenyl)sulfonyl]-7-Chloro-2,4(1H,3H)-Quinazolinedione(Compound 11)

[0108] 1.62 g (5.65 mmol) of3-t-butoxycarbonyl-methylaminobenzenesulfonamide and 1.73 g (5.65 mmol)of methyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in thesame way as in Preparation Example 7 to obtain 209 mg (yield 9%: 4steps) of the above-identified compound. Properties: colorless crystal,Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 3.86 (2H,s), 6.88 (1H, s), 7.12 (1H, s), 7.24 (1H, d), 7.30-7.38 (3H, m), 7.86(1H, d), 11.61 (1H, br).

Preparation Example 12 Synthesis of3-(3-Aminobenzenesulfonyl)-7-Chloro-2,4(1H,3H)-Quinazolinedione(Compound 12)

[0109] 3.5 g (12.9 mmol) of 3-t-butoxycarbonylamino-benzenesulfonamideand 3.9 g (12.8 mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilatewere treated in the same way as in Preparation Example 7 to obtain 2.2 g(yield 49%: 4 steps) of the above-identified compound. Properties:colorless crystal, Melting point; >200° C. (decomposition), PMR (δ ppm,DMSO-d₆): 5.72 (2H, s), 6.87 (1H, d), 7.12 (1H, s), 7.23-7.27 (2H, m),7.33 (1H, s), 7.86 (1H, d), 11.61 (1H, 5).

Preparation Example 13 Synthesis of2-{(3-[(7-Chloro-2,4(1H,3H)-Quinazolinedion-3-yl)sulfonyl]Phenylaminocarbonyl}Propionicacid (Compound 13)

[0110]100 mg (0.28 mmol) of Compound 12 was dissolved in 5 ml of THF,100 mg (1.0 mmol) of succinic anhydride was added, and the resultantmixture was heated and refluxed for 3 hours. The reaction solution wasconcentrated in vacuo and the crude product thus obtained wascrystallized with ethyl acetate-diethyl ether to obtain 120 mg (yield96%) of the above-identified compound. Properties: colorless crystal,Melting point: 187-188° C., PMR (δ ppm, DMSO-d₆): 2.54 (2H, d), 2.59(2H, d), 7.12 (1H, s), 7.24 (1H, d), 7.59 (1H, t), 7.80 (1H, d), 7.86(1H, d), 7.96 (1H, d), 8.41 (1H, s), 10.40 (1H, s), 11.63 (1H, br),12.10 (1H, br).

Preparation Example 14 Synthesis of 3-{3-[(7-Chloro-2,4(1H3H)-Quinazolinedion-3-yl)Sulfonyl]Phenyl}Acrylic Acid (Compound 14)

[0111] 1.54 g (5.44 mmol) of t-butyl 3-(3-aminosulfonyl)phenylacrylateand 1.66 g (5.44 mmol) of methyl4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way asin Preparation Example 7 to obtain 2.18 g (yield 81%) of methyl2-({[3-(3-t-butoxy-3-oxo-1-propenyl)benzenesulfonylamino]carbonyl}amino)-4-chlorobenzoate.Properties: colorless amorphous, PMR (δ ppm, CDCl₃): 1.53 (9H, s), 3.95(3H, s), 6.46 (1H, d), 7.05 (1H, d), 7.55 (1H, m), 7.57 (1H, d), 7.72(1H, m), 7.93 (1H, m), 8.04 (1H, m), 8.27 (1H, s), 8.46 (1H, d), 11.05(1H, br).

[0112] Then, from 2.18 g (4.4 mmol) of the resultant sulfonylureaproduct, in the same way, 698 mg (yield 37%: 3 steps) of theabove-identified compound was obtained. Properties: colorless crystal,Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 6.65 (1H,d), 7.12 (1H, s), 7.25 (1H, d), 7.69 (1H, d), 7.72 (1H, t), 7.87 (1H,d), 8.12 (2H, q), 8.37 (1H, s), 11.64 (1H, s).

Preparation Example 15 Synthesis of4-[(7-Chloro-2,4(1H,3H)-Quinazolinedion-3-yl)Sulfonyl]Salicylic Acid(Compound 15)

[0113] 1.0 g (3.66 mmol) of4-t-butoxycarbonyl-3-hydroxybenzenesulfonamide and 1.12 g (3.66 mmol) ofmethyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the sameway as in Preparation Example 7 to obtain 1.79 g (yield 100%) of methyl2-{[(4-t-butoxycarbonyl-3-hydroxybenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate.Properties: colorless amorphous, PMR (δ ppm, DMSO-d₆): 1.57 (9H, s),3.87 (3H, s), 7.14 (1H, d), 7.40-7.45 (2H, m), 7.85 (1H, d), 7.92 (1H,d), 8.32 (1H, d), 10.13 (1H, s), 10.82 (1H, S).

[0114] Then, from 1.78 g (3.66 mmol) of the resultant sulfonylureaproduct, in the same way, 370 mg (yield 25%: 3 steps) of theabove-identified compound was obtained. Properties: colorless crystal,Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 7.13 (1H,s), 7.26 (1H, d), 7.69 (1H, d), 7.87 (1H, d), 8.01 (1H, d), 11.67 (1H,S).

Preparation Example 16 Synthesis of4-[(7-Chloro-2,4(1H,3H)-Quinazolinedion-3-yl)Sulfonyl]Salicylic AcidMonosodium Aalt (Compound 16)

[0115] 50 mg (0.13 mmol) of Compound 15 was suspended in approximately 1ml of THF, then 126 μl of 1N sodium hydroxide aqueous solution was addeddropwise. The solution was confirmed to have become uniform, then 30 mlof water was added and the mixture freeze-dried to quantitatively obtainthe above-identified compound in an amorphous state in an amount of 52mg. Properties: colorless amorphous, PMR (δ ppm, CD₃OD): 7.11 (1H, s),7.19 (1H, d), 7.58 (1H, d), 7.63 (1H, s), 7.92 (1H, d), 8.03 (1H, d).

Preparation Example 17 Synthesis of4-[(7-Chloro-2,4(1H,3H)-Quinazolinedion-3-yl)Sulfonvl]Anthranilic Acid(Compound 17)

[0116] 2.84 g (6.99 mmol) of3-benzyloxycarbonylamino-4-t-butoxycarbonylbenzenesulfonamide and 2.67 g(6.99 mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate weretreated in the same way as in Preparation Example 8 to obtain 3.74 g(yield 77%) of benzyl2-{[(3-benzyloxycarbonylamino-4-t-butoxycarbonylbenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate.Properties: colorless amorphous, PMR (δ ppm, DMSO-d₆): 1.54 (9H, s),5.19 (2H, s), 5.34 (2H, s), 7.05 (1H, m), 7.34-7.58 (10H, m), 7.60 (1H,d), 7.90 (1H, d), 7.98 (1H, d), 8.50 (1H, br), 8.62 (1H, s), 10.00 (1H,br), 10.41 (1H, 5).

[0117] Then, from 3.74 g (5.39 mmol) of the resultant sulfonylurea, inthe same way, 690 mg (yield 30%: 2 steps) of t-butyl4-[(7-chloro-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]anthranilate wasobtained, then this was subjected to a similar debutylation reaction toobtain 503 mg (yield 84%) of the above-identified compound. Properties:colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm,DMSO-d₆): 7.14 (1H, s), 7.18 (1H, d), 7.25 (1H, d), 7.59 (1H, s), 7.87(1H, d), 7.89 (1H, d), 11.62 (1H, s).

Preparation Example 18 Synthesis of4-[(7-Chloro-2,4(1H,3H)-Quinazolinedion-3-yl)Sulfonyl]Anthranilic AcidMonosodium Salt (Compound 18)

[0118] 50 mg (0.13 mmol) of Compound 17 was suspended in approximately 1ml of THF, then 126 μl of 1N sodium hydroxide aqueous solution was addeddropwise. The solution was confirmed to have become uniform, then 30 mlof water was added and the mixture was freeze-dried to quantitativelyobtain the above-identified compound in an amorphous state in an amountof 52 mg. Properties: colorless amorphous, PMR (δ ppm, DMSO-d₆):7.11-7.22 (3H, m), 7.37 (1H, s), 7.83 (1H, d), 7.91 (1H, d).

Preparation Example 19 Synthesis of3-4-Hydroxvbenzenesulfonyl)-7-Chloro-2,4(1H,3H)-Quinazolinedione(Compound 19)

[0119] 1.50 g (7.03 mmol) of 4-allyloxybenzenesulfonyl isocyanate and1.2 g (7.03 mmol) of 4-chloroanthranilic acid were treated in the sameway as in Preparation Example 5 to obtain 1.5 g (yield 53%) of3-(4-allyloxybenzenesulfonyl)-7-chloro-2,4(1H,3H)-quinazolinedione. 500mg (1.27 mmol) thereof was similarly treated to obtain 405 mg of theabove-identified compound (yield 90%). Properties: colorless crystal,Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 6.98 (2H,d), 7.11 (1H, s), 7.23 (1H, d), 7.85 (1H, d), 8.00 (2H, d), 11.25 (1H,br).

Preparation Example 20 Synthesis of4-[(2.4(1H,3H)-Quinazolinedion-3-yl)Sulfonyl]Salicylic Acid (Compound20)

[0120] 618 mg (2.26 mmol) of4-t-butoxycarbonyl-3-hydroxybenzenesulfonamide and 613 mg (2.26 mmol) ofmethyl 2-N-phenoxycarbonylanthranilate were treated in the same way asin Preparation Example 17 to obtain 792 mg (yield 78%) of methyl2-{[(4-t-butoxycarbonyl-3-hydroxybenzene-sulfonylamino)carbonyl]amino}benzoate.Properties: colorless amorphous, PMR (δ ppm, CDCl₃): 1.60 (9H, s), 3.97(3H, s), 7.09 (1H, t), 7.49-7.52 (2H, m), 7.65 (1H, d), 7.90 (1H, d),8.01 (1H, dd), 8.33 (1H, d), 10.98 (1H, s), 11.18 (1H, s).

[0121] Then, from 790 mg (1.75 mmol) of the resultant sulfonylureaproduct, in the same way, 100 mg (yield 8%: 3 steps) of theabove-identified compound was obtained. Properties: colorless crystal,Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 7.13 (1H,d), 7.22 (1H, t), 7.63-7.69 (3H, m), 7.87 (1H, d), 8.01 (1H, d), 11.57(1H, s).

Preparation Example 21 Synthesis of5-[(7-Chloro-2,4(1H,3H)-Quinazolinedion-3-yl)Sulfonyl]Salicylic Acid(Compound 21)

[0122] 320 mg (1.17 mmol) of3-t-butoxycarbonyl-4-hydroxybenzenesulfonamide and 447 mg (1.17 mmol) ofbenzyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the sameway as in Preparation Example 17 to obtain 611 mg (yield 93%) of benzyl2-{[(3-t-butoxycarbonyl-4-hydroxybenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate.Properties: colorless amorphous, PMR (δ ppm, CDCl₃): 1.62 (9H, s), 5.35(2H, s), 7.01-7.05 (2H, m), 7.37-7.41 (5H, m), 7.96 (1H, d), 8.10 (1H,dd), 8.46-8.48 (2H, m), 10.99 (1H, s), 11.66 (1H, s).

[0123] Then, from 611 mg (1.09 mmol) of the resultant sulfonylureaproduct, in the same way, 114 mg (yield 33%: 3 steps) of theabove-identified compound was obtained. Properties: colorless crystal,Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 7.11 (1H,s), 7.19 (1H, d), 7.24 (1H, d), 7.86 (1H, d), 8.20 (1H, d), 8.56 (1H,s), 11.57 (1H, s).

Preparation Example 22 Synthesis of3-(3-Acetamide-4-Methoxvbenzenesulfonyl)-7-Chloro-2,4(1H,3H)-Quinazolinedione(Compound 22)

[0124] 500 mg (2.19 mmol) of 3-acetamide-4-methoxybenzenesulfonamide and836 mg (2.19 mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilatewere treated in the same way as in Preparation Example 8 to obtain 812mg (yield 70%) of benzyl2-{[(3-acetylamino-4-methoxybenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate.Properties: colorless amorphous, PMR (δ ppm, DMSO-d₆): 2.12 (3H, s),3.93 (3H, s), 5.36 (2H, s), 7.20 (1H, d), 7.24 (1H, d), 7.36-7.48 (5H,m), 7.69 (1H, d), 7.96 (1H, d), 8.24 (1H, s), 8.67 (1H, s), 9.39 (1H,s), 10.25 (1H, s), 12.11 (1H, br).

[0125] Then, from 611 mg (1.09 mmol) of the resultant sulfonylureaproduct, in the same way, 250 mg (yield 39%: 2 steps) of theabove-identified compound was obtained. Properties: colorless crystal,Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 2.12 (3H,s), 3.95 (3H, s), 7.12 (1H, s), 7.23 (1H, d), 7.30 (1H, d), 7.85 (1H,d), 7.89 (1H, d), 8.80 (1H, s), 9.42 (1H, s), 11.59 (1H, br).

Preparation Example 23 Synthesis of3-(3-Amino-4-Methoxybenzenesulfonyl)-7-Chloro-2,4(1H,3H)-Quinazolinedione(Compound 23)

[0126] 400 mg (1.40 mmol) of3-t-butoxycarbonylamino-4-methoxybenzenesulfonamide and 533 mg (1.40mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated inthe same way as in Preparation Example 17 to obtain 86 mg (yield 16%: 4steps) of the above-identified compound. Properties: colorless crystal,Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 3.81 (3H,s), 7.26-7.37 (5H, m), 7.77 (1H, s), 7.90 (1H, d), 7.94 (1H, d), 11.73(1H, s).

Preparation Example 24 Synthesis of7-Chloro-3-(4-Methoxy-3-Methylsulfonylaminobenzenesulfonyl)-2,4(1H,3H)-Quinazolinedione(Compound 24)

[0127] 500 mg (1.89 mmol) of4-methoxy-3-methylsulfonylaminobenzenesulfonamide and 722 mg (1.89 mmol)of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in thesame way as in Preparation Example 8 to obtain 888 mg (yield 83%) ofbenzyl 2-({[(4-methoxy-3-methylsulfonylamino)benzenesulfonylamino]carbonyl}amino)-4-chlorobenzoate. Properties: colorlessamorphous, PMR (δ ppm, DMSO-d₆): 2.12 (3H, s), 3.93 (3H, s), 5.36 (2H,s), 7.20 (1H, d), 7.24 (1H, d), 7.36-7.48 (5H, m), 7.69 (1H, d), 7.96(1H, d), 8.24 (1H, s), 8.67 (1H, s), 9.39 (1H, s), 10.25 (1H, s), 12.11(1H, br).

[0128] Then, from 880 mg (1.55 mmol) of the resultant sulfonylureaproduct, in the same way, 620 mg (yield 85%: 2 steps) of theabove-identified compound was obtained. Properties: colorless crystal,Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 3.04 (3H,s), 3.94 (3H, s), 7.11 (1H, s), 7.23 (1H, d), 7.34 (1H, d), 7.86 (1H,d), 7.99 (1H, d), 8.10 (1H, S).

Preparation Example 25 Synthesis of4-[(7-Chloro-2,4(1H,3H)-Quinazolinedion-3-yl)Sulfonyl]-1-Hydroxy-Naphthalene-2-CarboxylicAcid (Compound 25)

[0129] 323 mg (1.00 mmol) of3-t-butoxycarbonyl-4-hydroxy-1-naphthalenesulfonamide and 381 mg (1.00mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated inthe same way as in Preparation Example 17 to obtain 447 mg (yield 73%)of4-({[(2-benzyloxycarbonyl-5-chloroanilino)carbonyl]amino}sulfonyl)-1-hydroxy-2-naphthalenecarboxylicacid t-butyl ester. Properties: colorless amorphous, PMR (δ ppm,DMSO-d₆): 1.66 (9H, s), 5.34 (3H, s), 6.98 (1H, d), 7.35-7.48 (5H, m),7.66 (1H, m), 7.81 (1H, m), 7.89 (1H, d), 8.37 (2H, m), 8.44 (1H, s),8.71 (1H, d), 10.02 (1H, br), 12.52 (1H, br).

[0130] Then, from 445 mg (0.72 mmol) of the resultant sulfonylureaproduct, in the same way, 56 mg (yield 18%: 3 steps) of theabove-identified compound was obtained. Properties: colorless crystal,Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 7.08 (1H,s), 7.20 (1H, d), 7.63 (1H, t), 7.77 (1H, t), 7.84 (1H, d), 8.42 (1H,d), 8.51 (1H, d), 8.75 (1H, s), 11.57 (1H, s).

Preparation Example 26 Synthesis of5-[(7-Chloro-2,4(1H,3H)-Quinazolinedion-3-yl)Sulfonyl]Anthranilic Acid(Compound 26)

[0131] 834 mg (2.05 mmol) of4-benzyloxycarbonylamino-3-t-butoxycarbonylbenzenesulfonamide and 783 mg(2.05 mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate weretreated in the same way as in Preparation Example 17 to obtain 1.18 g(yield 83%) of benzyl2-{[(4-benzyloxycarbonylamino-3-t-butoxycarbonylbenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate.Properties: colorless amorphous, PMR (δ ppm, CDCl₃): 1.56 (9H, s), 5.22(2H, s), 5.37 (2H, s), 7.04 (1H, dd), 7.33-7.42 (10H, m), 7.97 (1H, d),8.14 (1H, d), 8.45 (1H, d), 8.60 (1H, d), 8.65 (1H, d), 11.01 (1H, S),11.11 (1H, s).

[0132] Then, from 1.17 g (1.69 mmol) of the resultant sulfonylureaproduct, in the same way, 404 mg (yield 60%: 3 steps) of theabove-identified compound was obtained. Properties: colorless crystal,Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 6.89 (1H,d), 7.11 (1H, s), 7.23 (1H, d), 7.85 (1H, d), 7.98 (1H, d), 8.51 (1H,s), 11.51 (1H, s).

Preparation Example 27 Synthesis of4-[(7-Methoxy-2,4(1H,3H)-Quinazolinedion-3-yl)Sulfonyl]Anthranilic Acid(Compound 27)

[0133] 500 mg (1.23 mmol) of3-benzyloxycarbonylamino-4-t-butoxycarbonylbenzenesulfonamide and 460 mg(1.22 mmol) of benzyl 4-methoxy-2-N-phenoxycarbonylanthranilate weretreated in the same way as in Preparation Example 17 to obtain 15 mg(yield 3.1%: 4 steps) of the above-identified compound. Properties:colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm,DMSO-d₆): 3.82 (3H, s), 6.58 (1H, S), 6.80 (1H, d), 7.16 (1H, d), 7.56(1H, s), 7.80 (1H, d), 7.90 (1H, d), 11.49 (1H, s).

Preparation Example 28 Synthesis of (±)-7-[(7-Chloro-2,4(1H,3H)-Quinazolinedion-3-yl)Sulfonyl]-2-oxo-1H,3H-Quinoline-3-Carboxylicacid (Compound 28)

[0134] 400 mg (1.23 mmol) of(±)-3-t-butoxycarbonyl-2-oxo-1H,3H-quinoline-7-sulfonamide and 468 mg(1.23 mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate weretreated in the same way as in Preparation Example 17 to obtain 649 mg(yield 86%) of8-({[(2-benzyloxycarbonyl-5-chloroanilino)carbonyl]jamino}sulfonyl)-2-oxo-1,2,3,4-tetrahydro-3-quinolinecarboxylic acid t-butyl ester. Properties: colorless amorphous, PMR (δppm, CDCl₃): 1.32 (9H, s), 3.18-3.30 (2H, m), 3.54 (1H, m), 5.35 (2H,s), 6.85 (1H, m), 7.00 (1H, m), 7.35-7.39 (5H, m), 7.87-7.96 (3H, m),8.47 (1H, m), 8.78 (1H, br), 10.92 (1H, br).

[0135] Then, from 640 mg (1.04 mmol) of the resultant sulfonylureaproduct, in the same way, 258 mg (yield 55%: 3 steps) of theabove-identified compound was obtained. Properties: colorless crystal,Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 3.23-3.31(2H, m), 3.59 (1H, t), 7.07 (1H, d), 7.12 (1H, s), 7.25 (1H, d), 7.86(1H, d), 7.96 (1H, d), 7.98 (1H, d), 10.84 (1H, s), 11.60 (1H, s).

Preparation Example 29 Synthesis of(±)-6-[(7-Chloro-2,4(1H,3H)-Quinazolinedion-3-yl)Sulfonyl]-3-oxo-1,4-Benzoxazine-2-CarboxylicAcid (Compound 29)

[0136] 300 mg (0.91 mmol) of(±)-2-t-butoxycarbonyl-3-oxo-1,4-benzoxazin-6-sulfonamide and 349 mg(0.91 mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate weretreated in the same way as in Preparation Example 17 to obtain 417 mg(yield 74%) of5-({[(2-benzyloxycarbonyl-5-chloroanilino)carbonyl]amino}sulfonyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylicacid t-butyl ester. Properties: colorless amorphous, PMR (δ ppm,DMSO-d₆): 1.29 (9H, s), 5.37 (2H, s), 5.42 (2H, s), 7.19-7.26 (2H, m),7.37-7.57 (7H, m), 7.97 (1H, d), 8.25 (1H, d), 10.27 (1H, s), 11.25 (1H,s), 12.22 (1H, br).

[0137] Then, from 417 mg (0.68 mmol) of the resultant sulfonylureaproduct, in the same way, 100 mg (yield 32%: 3 steps) of theabove-identified compound was obtained. Properties; colorless crystal,Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 5.47 (1H,s), 7.11 (1H, s), 7.24 (1H, d), 7.29 (1H, d), 7.76 (1H, s), 7.78 (1H,d), 7.86 (1H, d), 11.25 (1H, s), 11.62 (1H, S).

Preparation Example 30 Synthesis of4-[(7-Hydroxy-2,4(11H,3H)-Quinazolinedion-3-yl)Sulfonyl]Anthranilic Acid(Compound 30)

[0138] 620 mg (1.53 mmol) of3-benzyloxycarbonylamino-4-t-butoxycarbonylbenzenesulfonamide and 550 mg(1.51 mmol) of benzyl 4-hydroxy-2-N-phenoxycarbonylanthranilate weretreated in the same way as in Preparation Example 17 to obtain 25 mg(yield 4%: 4 steps) of the above-identified compound. Properties:colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm,DMSO-d₆): 6.48 (1H, s), 6.61 (1H, d), 7.14 (1H, d), 7.51 (1H, s), 7.70(1H, d), 7.90 (1H, d), 10.80 (1H, s), 11.39 (1H, s).

Preparation Example 31 Synthesis of 4-[(7-Chloro-2,4(1H,3H)-Quinazolinedion-3-yl)Sulfonyl]-2-N-Propionylanthranilic acid(Compound 31)

[0139] 840 mg (1.86 mmol) of Compound 17 was dissolved in 8 ml of1,4-dioxane, 240 μl (2.79 mmol) of propionyl chloride was addeddropwise, then the resultant mixture was stirred overnight at 60° C. Anexcess of water was added to the reaction solution and the mixture wasextracted with ethyl acetate. The organic layer thus obtained waswashed, dried, and concentrated to obtain a crude product of t-butyl4-[(7-chloro-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]-2-N-propionylanthranilate.The obtained crude product was stirred at room temperature in 3 ml oftrifluoroacetic acid for 1 hour, then the reaction solution wasconcentrated in vacuo to obtain a crude product. This was washed bydiethyl ether to obtain 400 mg (yield 48%: 2 steps) of theabove-identified compound. Properties: colorless crystal, Meltingpoint: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 1.10 (3H, t),2.45 (2H, dd), 7.11 (1H, s), 7.24 (1H, d), 7.85 (1H, d), 7.88 (1H, d),8.17 (1H, d), 9.18 (1H, s), 11.07 (1H, s), 11.63 (1H, s).

Preparation Example 32 Synthesis of4-[(6-chloro-2,4(1H,3H)-Quinazolinedion-3-yl) Sulfony]Anthranilic Acid(Compound 32)

[0140] 300 mg (0.74 mmol) of3-benzyloxycarbonylamino-4-t-butoxycarbonylbenzenesulfonamide and 310 mg(0.81 mmol) of benzyl 5-chloro-2-N-phenoxycarbonylanthranilate weretreated in the same way as in Preparation Example 17 to obtain 75 mg(yield 26%: 4 steps) of the above-identified compound. Properties:colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm,DMSO-d₆): 7.13-7.20 (2H, m), 7.56 (1H, s), 7.72 (1H, d), 7.82 (1H, s),7.90 (1H, d), 11.68 (1H, s).

Preparation Example 33 Synthesis of4-[(7-Chloro-2,4(1H,3H)-Quinazolinedion-3-yl)Sulfonyl]-2-N-Methanesulfonylanthranilicacid (Compound 33)

[0141] 200 mg (0.44 mmol) of Compound 17 was treated in the same way asin Preparation Example 3 to obtain 81 mg of t-butyl4-[(7-chloro-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]-2-N-methanesulfonylanthranilate.This was used to perform the same debutylation reaction to obtain 53 mg(yield 25%: 2 steps) of the above-identified compound. Properties:colorless crystal, Melting point: >200° c (decomposition), PMR (δ ppm,DMSO-d₆): 3.24 (3H, s), 7.11 (1H, s), 7.25 (1H, d), 7.85-7.91 (2H, m),8.23 (1H, d), 8.39 (1H, s), 11.05 (1H, br), 11.70 (1H, s).

Preparation Example 34 Synthesis of3-(3-Aminobenzenesulfonyl)-7-Chloro-2,4-(1H,3)QuinazolinedionMethanesulfonic Acid Salt (Compound 34)

[0142] 2.15 g (6.10 mmol) of compound 12 was dissolved in 65 ml of THFand 0.4 ml of methanesulfonic acid was added dropwise. To this solution,200 ml of ether was added and the resultant precipate was filtered toobtain 2.59 g (yield 95%) of the above-identified compound. Properties:colorless amorphous, PMR (δ ppm, DMSO-d₆): 2.35 (3H, s), 6.98 (1H, d),7.12 (1H, m), 7.25 (1H, m), 7.34 (2H, s), 7.43 (1H, m), 7.86 (1H, s),11.64 (1H, s).

Example 1 Measurement of Chymase Inhibitory Activity

[0143] Human heart chymase was purified according to the method of Urataet al. (J. Biol. Chem., 1990, 265, 22348). The inhibitory activity ofthe compound of the present invention was determined as follows.Purified enzyme was diluted with 0.1M tris-HCl buffer (pH=7.5), 1Msodium chloride, and 0.01% TritonX-100 to obtain an enzyme solutionhaving appropriate concentrations. Suc-Ala-Ala-Pro-Phe-MCA (PeptideInstitute Inc.) was dissolved in 10 mM dimethyl sulfoxide (hereinafterreferred to as DMSO) and diluted 20-fold with 0.1 M Tris-HCl buffer (pH7.5) containing 1 M sodium chloride and 0.01% Triton X-100 to anappropriate concentration to prepare substrate solution.

[0144] 5 μl of the test sample in DMSO was added to 75 μl of the enzymesolution and preincubated at 30° C. for 10 minutes. Then, 20 μl of thesubstrate solution was added to the test sample-enzyme mixture, andincubated at 30° C. Ten minutes later, 50 μl of 30% acetic acid wasadded to stop the enzymatic reaction, and the amount of AMC formed wasdetermined using a fluorophotometer. At the same time, 5 μl of DMSO instead of the test sample was added and reacted simultaneously as acontrol. The inhibitory activity to human chymase was calculated basedon the value of the control, and then the inhibition percentage and the50% inhibition concentration (IC₅₀) were determined.

[0145] The IC₅₀ values for representative compounds are shown in TableI. TABLE I Example No. IC₅₀ value (μM)  1 0.36  2 0.14  8 0.035 10 0.1712 0.44 13 0.3 16 0.84 17 0.14 18 0.14 21 0.34 22 0.3 24 0.32 27 4.0 291.7 32 1.5 34 0.36

Example 2 Effects of Chymase Inhibitor on Chymase Activity in Mice

[0146] A chymase inhibitor (Compound 18) was administeredintraperitoneally in ICR mice (8 weeks old, n=3). After 12 hours and 24hours, the chymase was extracted from the small intestines, tongues,back skins, front legs, and rear legs of the mice and the enzymaticactivity thereof was determined. The chymase was extracted using a 10 mMphosphate buffer including 2M KCl and 0.1% polyethylene octylphenylehter (Triton X-100) from the tissues. Chymase activity was determinedby measuring the rate of hydrolysis of synthesized substrateSuc-Phe-Pro-Phe-p-nitroanilide was administered in 24 hours in controlgroups.

[0147] Results

[0148] Administration of Compound 18 inhibited chymase activity in theintestines by approximately 80% compared with the group administeredsaline, whereas the inhibition by Compound 18 was about 50% in thetongue, back skin, and legs (see FIG. 1). These results show that theCompound 18 had an action in inhibiting chymase even in vivo.

Example 3 Determination of Chymase Activity in Tsk Mice, Model forScleroderma

[0149] Collagen content, thickness of subcutaneous fibrous layer, mastcell number, chymase activity and chymase mRNA were measured in the skinof Tsk mice (Rheum. Dis. Clin. North Am. 16, 153, 1990), and comparedwith the control mice (pallid mice) at the ages of 5, 10, and 20 weeks(n=6). The collagen content was determined by measuring hydroxyproline,the marker for collagen, using HPLC, whereas fibrous layer thickness wasdetermined by histological analysis with Azan staining followed bymeasuring the area of the fibrous layer using an image analysis system.The density of mast cells was calculated by counting the number of cellswith stained granules by toluidine blue staining. Chymase was extractedfrom the skin according to the method described previously (Arch.Dermatol. Res. 290, 553, 1998), and the activity determined as describedin Example 2. The mRNA for the skin chymase (MMCP-4) was measured onlyat 10 weeks of age by competitive RT-PCR method (Biotechniques 21, 268,1996).

[0150] Results

[0151] The amount of skin hydroxyproline in Tsk mice was about the sameas with the control pallid mice at 5 weeks of age, but was significantlyhigher than that of the controls at 10 and 20 weeks age (FIG. 2)(Student's t-test). Histological analysis revealed that there wasremarkable hypertrophy of the fibrous layer in Tsk mice compared withthe control mice at 5 weeks of age and that this difference becamegreater along with the increase in age (FIG. 3). The density of mastcells of the skin as well as the skin chymase activity in Tsk mice washigher than those of the control mice from 5 to 20 weeks age (FIG. 4 andFIG. 5). Further, the mRNA of the chymase MMCP-4 of 10 weeks aged micewas measured. The amount of mRNA of the MMCP-4 was significantly higherin value compared with that of the control mice (FIG. 6) as a result.

Example 4 Effect of Chymase Inhibitor against Tsk Mice. Model forScleroderma

[0152] 13-week old Tsk mice (n=5) were intra peritoneally administered achymase inhibitor (Compound 18) in a dosage of 50 mg/kg/day once a dayevery day for 2 weeks. Five hours after the final administration, thedegree of hypertrophy of the subcutaneous fibrous layer and the skinchymase activity were measured and compared with the values of the groupadministered saline. These parameters were measured in the same way asin Example 3.

[0153] Results

[0154] Pathohistological analysis revealed that the thickness of thesubcutaneous fibrous layer in Tsk mice administered the Compound 18 wasabout 60% of that for the group administered saline (FIG. 7). On theother hand, the chymase activity in the group administered Compound 18was 57% of that of the group administered saline (FIG. 8). These resultsshow that a chymase inhibitor normalizes the abnormalities of theconnective tissue accumulation in various fibrotic diseases and isuseful for the prevention or treatment of fibrogenesis.

Example 5 Change in Hydroxyproline Content in Luna in Bleomycin-InducedPulmonary Fibrosis Model

[0155] Pulmonary fibrosis was induced by intratracheal administration ofbleomycin (Nippon Kayaku) to 10 week old male ICR mice (Charles RiverJapan) under anesthesia (n=10). That is, bleomycin (0.04 mg or 0.08 mg)was suspended in 50 μl of saline and administered into the airways usinga 100 μl syringe (made by Hamilton Co.) Two weeks after theadministration of bleomycin, the lungs were excised and the amount ofhydroxyproline, an indicator of tissue collagen, was assayed accordingto the method as described previously (Anal. Biochem. 19, 249, 1967).Further, the amount of hydroxyproline was expressed as an amount perlung. Further, mice similarly administered saline instead of bleomycinwere used as a control (n=10).

[0156] Results

[0157] Administration of bleomycin increased hydroxyproline content inthe lung in a dose-dependent manner (FIG. 9). The hydroxyprolinecontents were 1.15-fold and 1.25-fold at 0.04 mg/mouse and 0.08mg/mouse, respectively, as compared with the saline group (p<0.05,p<0.01, respectively, Dunnett's test). This result shows thatintratracheal administration of bleomycin induces lung fibrosis. In thefollowing tests, the dosage of bleomycin was made of 0.08 mg.

Example 6 Change in Pulmonary Chymase Activity in Bleomycin-InducedPulmonary Fibrosis

[0158] Pulmonary fibrosis was induced by administration of 0.08 mg ofbleomycin to mouse airways in accordance with the method described inExample 5 (n=3). The lungs were excised 2 weeks after administration,and the chymase activity was measured by the method described in Example3. Note that mice similarly administered saline instead of bleomycinwere used as the control (n=3).

[0159] Results

[0160] The pulmonary chymase activity of mice administered bleomycin wassignificantly higher than that of mice administered saline (see FIG.10). The activity of the group administered bleomycin was about 4.5times that of the group administered saline (p<0.05, Student's t-test).The above findings that chymase activity increases in pulmonary fibrosismodel suggests that chymase is involved in pathogenesis of pulmonaryfibrosis.

Example 7 Effects of Chymase Inhibitor in Bleomycin-Induced PulmonaryFibrosis Model

[0161] Pulmonary fibrosis was induced in accordance with the methoddescribed in Example 5 (n=10) and the amount of hydroxyproline inpulmonary tissue was assayed in the same way as in Example 5 in order toinvestigate the effect of a chymase inhibitor (Compound 34) on pulmonaryfibrosis. Further, the chymase inhibitor was suspended in salinecontaining 0.5% hydroxypropyl cellulose (HPC/saline) and administeredintraperitoneally at a dose of 10 mg/kg or 50 mg/kg once a day for fivedays a week over 2 weeks, starting immediately after the bleomycinadministration. Further, a group similarly administered bleomycin butadministered HPC/saline instead of compound 34 was used as the control.

[0162] Results

[0163] The chymase inhibitor (Compound 34) at a dose of 50 mg/kgsignificantly suppressed the increase of the amount of hydroxyproline inthe lung caused by the administration of bleomycin (p<0.05, Dunnett'stest). This rate of suppression was about 46% (FIG. 11). Compound 34 at10 mg/kg exhibited little effect in this model.

[0164] In summary, the studies have been conducted using animal modelsfor scleroderma (fibrosis of the skin) and pulmonary fibrosis in orderto elucidate the usefulness of a chymase inhibitor in various types offibrosis. The results show that the number of mast cells as well aschymase activity and its mRNA are increased in Tsk mice as compared withthe control mice along with the increase of skin fibrous layer (Example3). The administration of the chymase inhibitor Compound 18 suppressedthe chymase activity and significantly suppressed the increase of theskin fibrous layer (Example 4). Further, in a bleomycin pulmonaryfibrosis model, there was not only an increase in the amount ofhydroxyproline in the lung, the marker for pulmonary fibrosis (Example5), but also an increase in chymase activity in the lung (Example 6).The administration of the chymase inhibitor Compound 34 suppressed theincrease in the amount of hydroxyproline (Example 7). These resultssuggest that a chymase inhibitor alleviates extracellular matrixdysbolism and is useful for the prevention or treatment of various typesof fibrosis including scleroderma and pulmonary fibrosis.

Formulation Example 1 Production of Tablets

[0165] 100.0 g of Compound 1 was mixed with microcrystalline cellulosein an amount of 22.5 g and magnesium stearate in an amount of 2.5 g andthen tabletized by a single-action type tabletizing machine to producetablets each containing 200 mg of Compound 1 and having a diameter of 9mm and a weight of 250 mg.

Formulation Example 2 Production of Granules

[0166] 30 g of Compound 1 was mixed well with lactose in an amount of265 g and magnesium stearate in an amount of 5 g. The mixture waspressed molded, then pulverized and the granules sieved to obtainexcellent 10% granules of 20 to 50 mesh.

Formulation Example 3 Production of Suppository

[0167] Vitepsol H-15 (made by Dynamite Nobel Co.) was warmed to melt. Tothis was added Compound 1 to a concentration of 12.5 mg/ml. This washomogeneously mixed, then was added in 2 ml amounts to a rectalsuppository mold and cooled to obtain rectal suppositories eachcontaining 25 mg of the Compound 1.

INDUSTRIAL APPLICABILITY

[0168] According to the present invention, a chymase inhibitor caneffectively prevent and/or treat fibrosis in the skin and other organsthrough its effect of alleviating extracellular matrix dysbolism.

1. A medicament for the prevention or treatment of fibrosis involvingextracellular matrix dysbolism having a chymase inhibitor as aneffective ingredient.
 2. A medicament for prevention or treatmentaccording to claim 1, wherein the fibrosis involving extracellularmatrix dysbolism is at least one disease selected from the groupcomprised of scleroderma, pulmonary fibrosis, benign prostatomegaly,myocardial fibrogenesis following myocardial infarction, myocardialfibrosis, musculoskeletal fibrosis, post-surgical adhesion, hypertropicscars and keloids, cirrhosis, hepatic fibrosis, renal fibrosis, fibrousvascular disorders, and complications of diabetes such as retinitis dueto fibrous microvasculitis, neurosis, nephropathy, and peripheralarteritis or a condition related to the same.
 3. A pharmaceuticalcomposition for the prevention or treatment of fibrosis involvingextracellular matrix dysbolism containing an amount of a chymaseinhibitor for alleviating extracellular matrix dysbolism and apharmaceutically acceptable vehicle.
 4. A pharmaceutical compositionaccording to claim 3, wherein the fibrosis involving extracellularmatrix dysbolism is at least one disease selected from the groupcomprised of scleroderma, pulmonary fibrosis, benign prostatomegaly,myocardial fibrogenesis following myocardial infarction, myocardialfibrosis, musculoskeletal fibrosis, post-surgical adhesion, hypertropicscars and keloids, cirrhosis, hepatic fibrosis, renal fibrosis, fibrousvascular disorders, and complications of diabetes such as retinitis dueto fibrous microvasculitis, neurosis, nephropathy, and peripheralarteritis or a condition related to the same.
 5. A medicament foralleviating extracellular matrix dysbolism having a chymase inhibitor asan effective ingredient.
 6. A medicament for the prevention or treatmentas claimed in claim 1 or 2, wherein the chymase inhibitor is aquinazoline derivative having the following formula (I) and apharmaceutically acceptable salt thereof:

wherein the ring A represents an aryl group; R¹ represents a hydroxylgroup, an amino group, a C₁ to C₄ lower alkylamino group which may besubstituted with a carboxylic acid group, a C₇ to C₁₀ lower aralkylaminogroup which may be substituted with a carboxylic acid group, an aminogroup acylated with a C₁ to C₄ lower aliphatic acid which may besubstituted with a carboxylic acid group, an amino group acylated withan aromatic ring carboxylic acid which may be substituted with acarboxylic acid group, an amino group acylated with a heteroaromaticring carboxylic acid which may be substituted with a carboxylic acidgroup, an amino group sulfonylated with a C₁ to C₄ lower alkanesulfonicacid which may be substituted with a carboxylic acid group, an aminogroup sulfonylated with an aromatic ring sulfonic acid which may besubstituted with a carboxylic acid group, an amino group sulfonylatedwith a heteroaromatic ring sulfonic acid which may be substituted with acarboxylic acid group, a C₁ to C₄ lower alkyl group substituted with acarboxylic acid group, or a C₂ to C₄ lower alkylene group which may besubstituted with a carboxylic acid group; R² and R³ may be the same ordifferent and represent a hydrogen atom, an unsubstituted or substitutedC₁ to C₄ lower alkyl group, a halogen atom, a hydroxyl group, a C₁ to C₄lower alkoxyl group, an amino group, an unsubstituted or substituted C₁to C₄ lower alkylamino group, an unsubstituted or substituted C₇ to C₁₀aralkylamino group, an amino group acylated with a C₁ to C₄ loweraliphatic acid which may be substituted with a carboxylic acid group, anamino group acylated with an aromatic ring carboxylic acid which may besubstituted with a carboxylic acid group, an amino group acylated with aheteroaromatic ring carboxylic acid which may be substituted with acarboxylic acid group, an amino group sulfonylated with a C₁ to C₄ loweralkanesulfonic acid which may be substituted with a carboxylic acidgroup, an amino group sulfonylated with an aromatic ring sulfonic acidwhich may be substituted with a carboxylic acid group, an amino groupsulfonylated with a heteroaromatic ring sulfonic acid which may besubstituted with a carboxylic acid group, or a carboxylic acid group orwhen the ring A is a benzene ring, R¹ and R² may form, together with thesubstituting benzene ring, a fused heterocyclic ring which may besubstituted with a carboxylic acid and in which the carbon atom in thering may form a carbonyl group and R³ is the same as defined above; andX represents a hydrogen atom, a C₁ to C₄ lower alkyl group, a C₁ to C₄lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, ora nitro group.
 7. A pharmaceutical composition as claimed in claim 3 or4, wherein the chymase inhibitor is a quinazoline derivative having thefollowing formula (I) and a pharmaceutically acceptable salt thereof:

wherein the ring A represents an aryl group; R¹ represents a hydroxylgroup, an amino group, a C₁ to C₄ lower alkylamino group which may besubstituted with a carboxylic acid group, a C₇ to C₁₀ lower aralkylaminogroup which may be substituted with a carboxylic acid group, an aminogroup acylated with a C₁ to C₄ lower aliphatic acid which may besubstituted with a carboxylic acid group, an amino group acylated withan aromatic ring carboxylic acid which may be substituted with acarboxylic acid group, an amino group acylated with a heteroaromaticring carboxylic acid which may be substituted with a carboxylic acidgroup, an amino group sulfonylated with a C₁ to C₄ lower alkanesulfonicacid which may be substituted with a carboxylic acid group, an aminogroup sulfonylated with an aromatic ring sulfonic acid which may besubstituted with a carboxylic acid group, an amino group sulfonylatedwith a heteroaromatic ring sulfonic acid which may be substituted witha, carboxylic acid group, a C₁ to C₄ lower alkyl group substituted witha carboxylic acid group, or a C₂ to C₄ lower alkylene group which may besubstituted with a carboxylic acid group; R² and R³ may be the same ordifferent and represent a hydrogen atom, an unsubstituted or substitutedC₁ to C₄ lower alkyl group, a halogen atom, a hydroxyl group, a C₁ to C₄lower alkoxyl group, an amino group, an unsubstituted or substituted C₁to C₄ lower alkylamino group, an unsubstituted or substituted C₇ to C₁₀aralkylamino group, an amino group acylated with a C₁ to C₄ loweraliphatic acid which may be substituted with a carboxylic acid group, anamino group acylated with an aromatic ring carboxylic acid which may besubstituted with a carboxylic acid group, an amino group acylated with aheteroaromatic ring carboxylic acid which may be substituted with acarboxylic acid group, an amino group sulfonylated with a C₁ to C₄ loweralkanesulfonic acid which may be substituted with a carboxylic acidgroup, an amino group sulfonylated with an aromatic ring sulfonic acidwhich may be substituted with a carboxylic acid group, an amino groupsulfonylated with a heteroaromatic ring sulfonic acid which may besubstituted with a carboxylic acid group, or a carboxylic acid group orwhen the ring A is a benzene ring, R¹ and R² may form, together with thesubstituting benzene ring, a fused heterocyclic ring which may besubstituted with a carboxylic acid and in which the carbon atom in thering may form a carbonyl group and R³ is the same as defined above; andX represents a hydrogen atom, a C₁ to C₄ lower alkyl group, a C₁ to C₄lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, ora nitro group.
 8. A medicament for alleviating extra cellular matrixdysbolism as claimed in claim 5, wherein the chymase inhibitor is aquinazoline derivative having the following formula (I) and apharmaceutically acceptable salt thereof:

wherein the ring A represents an aryl group; R¹ represents a hydroxylgroup, an amino group, a C₁ to C₄ lower alkylamino group which may besubstituted with a carboxylic acid group, a C₇ to C₁₀ lower aralkylaminogroup which may be substituted with a carboxylic acid group, an aminogroup acylated with a C₁ to C₄ lower aliphatic acid which may besubstituted with a carboxylic acid group, an amino group acylated withan aromatic ring carboxylic acid which may be substituted with acarboxylic acid group, an amino group acylated with a heteroaromaticring carboxylic acid which may be substituted with a carboxylic acidgroup, an amino group sulfonylated with a C₁ to C₄ lower alkanesulfonicacid which may be substituted with a carboxylic acid group, an aminogroup sulfonylated with an aromatic ring sulfonic acid which may besubstituted with a carboxylic acid group, an amino group sulfonylatedwith a heteroaromatic ring sulfonic acid which may be substituted with acarboxylic acid group, a C₁ to C₄ lower alkyl group substituted with acarboxylic acid group, or a C₂ to C₄ lower alkylene group which may besubstituted with a carboxylic acid group; R² and R³ may be the same ordifferent and represent a hydrogen atom, an unsubstituted or substitutedC₁ to C₄ lower alkyl group, a halogen atom, a hydroxyl group, a C₁ to C₄lower alkoxyl group, an amino group, an unsubstituted or substituted C₁to C₄ lower alkylamino group, an unsubstituted or substituted C₇ to C₁₀aralkylamino group, an amino group acylated with a C₁ to C₄ loweraliphatic acid which may be substituted with a carboxylic acid group, anamino group acylated with an aromatic ring carboxylic acid which may besubstituted with a carboxylic acid group, an amino group acylated with aheteroaromatic ring carboxylic acid which may be substituted with acarboxylic acid group, an amino group sulfonylated with a C₁ to C₄ loweralkanesulfonic acid which may be substituted with a carboxylic acidgroup, an amino group sulfonylated with an aromatic ring sulfonic acidwhich may be substituted with a carboxylic acid group, an amino groupsulfonylated with a heteroaromatic ring sulfonic acid which may besubstituted with a carboxylic acid group, or a carboxylic acid group orwhen the ring A is a benzene ring, R¹ and R² may form, together with thesubstituting benzene ring, a fused heterocyclic ring which may besubstituted with a carboxylic acid and in which the carbon atom in thering may form a carbonyl group and R³ is the same as defined above; andX represents a hydrogen atom, a C₁ to C₄ lower alkyl group, a C₁ to C₄lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, ora nitro group.